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Progressive paralysis in transgenic rats conditionally expressing a mutant human TDP gene.

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posted on 26.03.2010, 02:11 by Hongxia Zhou, Cao Huang, Han Chen, Dian Wang, Carlisle P. Landel, Pedro Yuxing Xia, Robert Bowser, Yong-Jian Liu, Xu Gang Xia

(A) Schematic diagram shows the structure of the inducible mutant TDP transgene (TRE-TDP-43M337V). Expression of the mutant TDP transgene depends on tTA activation and can be suppressed by Dox, which binds to tTA and renders it inactive. (B) Immunoblotting detected a robust expression of the transgene in the spinal cord of P20 rats. Membranes were probed sequentially with antibodies against human TDP-43 (generated in-house), human and rat TDP-43 (ProteinTech), and rat GAPDH. M337V: transgenic rats carrying the conditional mutant TDP (TRE-TDP-43M337V) and CAG-tTA transgenes; WT: transgenic rat carrying the mini normal human TDP transgene (miniTDP-43WT); NT: nontransgenic littermate of the WT transgenic rat; *, a weak nonspecific band. (C) Photo of a mutant TDP transgenic rat (line 7) paralyzed at P40. (D) Graphs show the probability of disease onset, defined as an unrecoverable reduction in running time on a Rotarod. Disease onset for line 16 was not plotted, since these animals experienced early paralysis with rapid progression and accurate definition of disease onset was technically difficult. (E) Survival analysis revealed that lifespan was remarkably reduced in the mutant TDP transgenic rats. Rats were euthanized and counted as dead when two or more legs became paralyzed. Male and female rats of line 16 were combined as one group because disease progression between each gender was indistinguishable. Definition of symbols in (D,E): , normal TDP transgenic rats carrying the miniTDP-43WT transgene (line 4; n = 9); • and ○, mutant male (•, n = 10) and female (○, n = 12) transgenic rats carrying the TRE-TDP-43M337V (line 7) and CAGtTA transgenes; , mutant TDP transgenic rats carrying the TRE-TDP-43M337V (line 16) and the CAGtTA transgenes (n = 14). All breeding female rats were given Dox in drinking water (50 µg/ml) until 4 days before delivery.

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